This Specialized Program of Research Excellence (SPORE) in Endometrial Cancer is submitted by Washington University in St. Louis, the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. It includes four research projects, three supportive cores, and research and career development programs. This proposal brings together basic and applied investigators to conduct innovative and diverse translational investigations aimed at preventing, diagnosing and treating endometrial cancer. The four projects in our application have been carefully designed to have significant potential to change clinical practice within five years. Project 1: FGFR2 as therapeutic target in endometrial cancer Project 2: Methylation markers for prognosis in endometrioid endometrial cancers Project 3: Identifying inherited endometrial cancer &the environmental and genetic factors contributing to somatic loss of mismatch repair Project 4: Novel effectors of ERK signaling and their potential roles in the treatment of endometrial cancer The four projects represent carefully chosen marriages between selected endometrial cancer research priorities and the strengths of Washington University and our collaborators. The critical objectives that we have chosen to focus on are to: 1) improve the treatment of patients with persistent or recurrent endometrial cancer using a molecularly targeted therapy and determine if upfront adjuvant biologic therapies hold promise for improving outcomes in the general endometrial cancer population;2) develop prognostic markers to help guide the treatment of women with the most common form of uterine tumors, endometrioid endometrial cancer;3) optimize detection of those women with inherited forms of endometrial cancer so they and their at-risk family members can receive risk-appropriate (intensified) cancer surveillance;and 4) elucidate the role novel effectors of ERK signaling play in uterine cancer and assess opportunities for targeting these in the treatment of endometrial cancers. Three Cores will support these projects: Administration, Tissue &Pathology, and Biostatistics. The Developmental Research Program will support a pathway for continued identification and support of diverse research that could replace or improve current projects, and a Career Development Program will recruit and support candidates committed to training in translational research in endometrial cancer.